Hypercholesterolemia is known to be one of the prime risk factors of cardiovascular disease such as arteriosclerosis, and there is still no effective antihypercholesterolemic agent commercially available that has found wide patient acceptance. The bile acid sequestrants seem to be moderately effective but they must be consumed in large quantities, i.e. several grams at a time and they are not very palatable.
There are agents known, however, that are very active antihypercholesterolemic agents that function by limiting cholesterol biosynthesis by inhibiting the enzyme, HMG-CoA reductase. These agents include the natural fermentation products compactin and mevinolin and a variety of semi-synthetic and totally synthetic analogs thereof. The naturally occurring compounds and their semi-synthetic analogs have the following general structural formulae: ##STR3## wherein: R.sup.3 is hydrogen, C.sub.1-5 alkyl or C.sub.1-5 alkyl substituted with a member of the group consisting of phenyl, dimethylamino, or acetylamino;
R.sup.4 is ##STR4## wherein Q is ##STR5## R.sup.5 is H or OH: R.sup.6 is hydrogen or methyl; and a, b, c, and d represent optional double bonds, especially where b and d represent double bonds or a, b, c, and d are all single bonds. PA0 R is hydrogen or ##STR11## R.sup.1 is hydrogen or methyl; R.sup.2 is hydrogen or methyl; and PA0 R.sup.3 is hydrogen, C.sub.1-5 alkyl or C.sub.1-5 alkyl substituted with a member of the group consisting of phenyl, dimethylamino, or acetylamino; and PA0 the dotted lines at a, b and c represent optional double bonds and pharmaceutically acceptable salts of the compounds (II) in which R.sup.3 is hydrogen. PA0 1. Preparation of liver microsomal pellets. PA0 2. Assay of the pellet for HMG-CoA reductase activity. FNT Reference: 1. Alberts, et al., Proceedings of the National Academy of Science, Vol. 77, pp. 3957-61 (1980). PA0 Buffer I (for homogenization) PA0 Buffer I + EDTA (for washing pellet) PA0 Procedure: all operation at 4.degree. C. PA0 Buffer A+50% glycerol PA0 Buffer A PA0 Porter Buffer PA0 Buffer B PA0 Procedure: all operations are carried out at room temperature
U.S. Pat. No. 4,517,373 discloses semi-synthetic hydroxy containing compounds represented by the above general formula wherein R.sup.4 is ##STR6##
U.S. Pat. No. 4,346,227 and U.S. Pat. No. 4,448,979 also disclose semi-synthetic hydroxy containing compounds represented by the above general formula wherein R.sup.4 is ##STR7##
U.S. Pat. No. 4,376,863 discloses a fermentation product isolated after cultivation of a microorganism belonging to the genus Aspergillus which has a hydroxy containing butyryloxy side chain and is represented by the above general formula wherein R.sup.4 is ##STR8##
Japanese unexamined patent application No. J59-122,483-A discloses a semi-synthetic hydroxy-containing compound represented by the above general formula wherein R.sup.4 is ##STR9##